Transdermal transport device with suction

ABSTRACT

A transdermal transport device includes a reservoir for holding a formulation of an active principle, and one or more needles. Each needle has a bore through which the formulation is transported between the reservoir and a biological body, and has an end portion that is substantially aligned in a plane parallel to a surface of the biological body when the device is placed on the surface. The device also includes a vacuum generator which creates a suction to draw a portion of the surface beyond the plane of the end portions to enable the end portions to penetrate the portion of the surface as the needles are translated along an axis that is substantially parallel to the plane.

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/338,425, filed Oct. 26, 2001, and U.S. ProvisionalApplication No. 60/399,489, filed Jul. 29, 2002.

[0002] The entire contents of the above applications are incorporatedherein by reference.

BACKGROUND

[0003] Delivery of drugs to a patient is performed in a number of ways.For example, intravenous delivery is by injection directly into a bloodvessel; intraperitoneal delivery is by injection into the peritoneum;subcutaneous delivery is under the skin; intramuscular is into a muscle;and orally is through the mouth. One of the easiest methods for drugdelivery, and for collection of body fluids, is through the skin.

[0004] Skin is the outermost protective layer of the body. It iscomposed of the epidermis, including the stratum corneum, the stratumgranulosum, the stratum spinosum, and the stratum basale, and thedermis, containing, among other things, the capillary layer. The stratumcorneum is a tough, scaly layer made of dead cell tissue. It extendsaround 10-20 microns from the skin surface and has no blood supply.Because of the density of this layer of cells, moving compounds acrossthe skin, either into or out of the body, can be very difficult.

[0005] The current technology for delivering local pharmaceuticalsthrough the skin includes both methods that use needles or other skinpiercing devices and methods that do not use such devices. Those methodsthat do not use needles typically involve: (a) topical applications, (b)iontophoresis, (c) electroporation, (d) laser perforation or alteration,(e) carriers or vehicles, which are compounds that modify the chemicalproperties of either the stratum corneum and/or the pharmaceutical, (f)physical pretreatment of the skin, such as abrasion of the stratumcorneum (e.g. repeatedly applying and removing adhesive tape), and (g)sonophoresis, which involves modifying the barrier function of stratumcorneum by ultrasound.

[0006] Topical applications, such as a patch, or direct application of apharmaceutical to the skin, depend on diffusion or absorption throughthe skin. These methods of transdermal transport are not widely usefulbecause of the limited permeability of the stratum corneum. Althoughtechniques such as those listed above have been developed to enhance theeffectiveness of topical applications, topical applications still cannotprovide optimum transdermal transport.

[0007] On the other hand, invasive procedures, such as use of needles orlances, effectively overcome the barrier function of the stratumcorneum. However, these methods suffer from several major disadvantages:pain, local skin damage, bleeding, and risk of infection at theinjection site, and creation of contaminated needles or lances that mustbe disposed of. These methods also usually require a trainedadministrator and are not suitable for repeated, long-term, orcontrolled use.

[0008] Additionally, drug delivery through the skin has been relativelyimprecise in both location and dosage of the pharmaceutical. Some of theproblems include movement of the patient during administration, deliveryof incomplete dosages, difficulties in administering more than onepharmaceutical at the same time, and difficulties in delivering apharmaceutical to the appropriate part of the skin. Drugs havetraditionally been diluted to enable handling of the proper dosages.This dilution step can cause storage as well as delivery problems. Thus,it would be advantageous to be able to use small, precise volumes ofpharmaceuticals for quick, as well as long-term, delivery through theskin.

SUMMARY

[0009] The present invention implements an effective, multi-applicationvacuum generator which when combined with a microneendle transportdevice secures the device to the skin of a biological body. Such acombination provides painless, precision insertion, controlled depthpenetration, and a variable, programmable delivery profile of aformulation of an active principle at commercially viable costs.

[0010] In one embodiment, a transdermal transport device includes areservoir for holding a formulation of an active principle, and one ormore needles. Each needle has a bore through which the formulation istransported between the reservoir and a biological body, and has an endportion that is substantially aligned in a plane parallel to a surfaceof the biological body when the device is placed on the surface. Thedevice also includes a vacuum generator which creates a suction to drawa portion of the surface beyond the plane of the end portions to enablethe end portions to penetrate the portion of the surface as the needlesare translated along an axis that is substantially parallel to theplane.

[0011] In certain embodiments, the vacuum is used to secure the deviceto the surface of the body. The vacuum can be turned off after theneedles penetrate the skin. In particular embodiments, the needles arerotated about an axis that is substantially perpendicular to the plane.Other embodiments are directed to methods of using the vacuum generator.

[0012] Some embodiments of the invention may have one or more of thefollowing advantages. Particularly in regards to ease of use, theautomated/mechanical system of the microneedle device reduces the errorand uncertainty usually introduced by manual application. Very little(if any) pain, local damage, bleeding, or risk of infection is caused bythe microneedles. Additionally, no special training or expertise isrequired to use the microneedle transport device. The device may furtherbe adapted for disposable single-use, partial or full reuse, short orlong-term use, or continuous or intermittent transport, or somecombination thereof.

[0013] Since a precise amount of volume of drug can be delivered, a lowvolume of drug is wasted. In addition to delivering a precise volume ofdrug with a variety of delivery profiles, the device is able to delivera range of drugs. For example, the formulation may be a liquid, or anon-liquid that is reconstituted at delivery, or some combinationthereof.

[0014] The device provides reduced pain as compared to traditionalhypodermic injections, with minimal air injected under the skin. A userof the device is able to verify drug, dosing, expiration, etc. with, forexample, a computer server via the internet. The suction or vacuumgenerator provides a convenient way of initially securing the device tothe biological body. The device is small, portable, inexpensive, andeasy to use, and, hence, increases patient compliance. In addition,since the vacuum is applied before the needles penetrate the skin, themicroneedles are protected within the base portion so that exposure tocontamination and/or accidental contact with a patient or medicalclinician is eliminated or minimized.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

[0016]FIG. 1 is a side schematic view of an applicator with atransdermal transport device in accordance with the invention.

[0017]FIG. 2A is a cross-sectional view of the transdermal transportdevice shown in FIG. 1.

[0018]FIG. 2B is a top view of the transdermal transport device shown inFIG. 1.

[0019]FIG. 2C is a bottom view of the transdermal transport device shownin FIG. 1.

[0020]FIG. 2D is a close-up view of a suction port shown in FIG. 2Cillustrating a microneedle in retracted and protracted states.

[0021]FIG. 3 is a close-up view of a tip of a microneedle of thetransdermal transport device shown in FIG. 1 shown penetrating the skinof a patient and dispensing a drug into the patient.

[0022]FIG. 4 is a close-up view of the tip of a microneedle of thetransdermal transport device shown in FIG. 1.

[0023]FIG. 5 is a side view of an alternative embodiment of amicroneedle in accordance with the invention.

[0024]FIG. 6A is a graph of the insertion force of a microneedle versusthe penetration depth of the microneedle.

[0025] FIGS. 6B-6I is a sequence of graphs of the insertion force of amicroneedle versus the penetration depth of the microneedle fordifferent diameter needles.

[0026]FIG. 7A is a view of an actuator of the transdermal transportdevice shown in FIG. 2A.

[0027]FIG. 7B is a graph of the voltage requirements of the actuatorshown in FIG. 7A with stainless steel electrodes.

[0028]FIG. 7C is a graph of the voltage requirements of the actuatorshown in FIG. 7A with Nichrome electrodes.

[0029]FIG. 8A is schematic of a circuit formed with electrodes of animpedance sensor of the transdermal transport device shown in FIG. 1 andthe skin of a patient.

[0030]FIG. 8B is a schematic diagram of a circuit used for the impedancesensor in accordance with the invention.

[0031]FIG. 9A is a graph of the magnitude of the impedance measured bythe impedance sensor of FIG. 8A versus frequency.

[0032]FIG. 9B is a graph of the impedance versus the penetration depth.

[0033]FIG. 10 is a cross-sectional view of an alternative embodiment ofthe transdermal transport device.

[0034]FIG. 11 is a cross-sectional view of yet another alternativeembodiment of the transdermal transport device.

DETAILED DESCRIPTION OF THE INVENTION

[0035] A description of preferred embodiments of the invention follows.

[0036] Referring to FIG. 1, there is shown a transdermal transportdevice 10 mounted to a coupling 11 of an applicator 12 which is used toattach the transport device 10 to the skin of a biological body, such asa human patient. Furthermore, the applicator 12 activates the device 10to initiate the transport process before being disengaged from thedevice.

[0037] The device 10 includes an array of microneedles 14 for piercingthe outer layers of skin of the patient and for delivering a formulationof an active principle such as pharmaceuticals through the skin toprovide accurate delivery of the pharmaceuticals to the patient.Moreover, because of the shape and size of the needles and the minimaldepth of penetration of the needles, contact between the needles and thenerve endings beneath the outer layer of the skin is minimized so thatpain is reduced or absent in the patient. The pharmaceutical may be aliquid formulation, or it may be one or more nonliquid drugs that arereconstituted just before delivery.

[0038] The applicator 12 is powered by a set of batteries 16 andcontrolled by an embedded processor 18 positioned within a housing 20which holds various other internal components of the applicator. Adisplay 22, such as an LCD, mounted on top of the housing 20communicates to a user the operating parameters of the transport device10 and the applicator 12. The applicator 12 is able to communicate witha mother unit such as a PC and/or through the internet with acommunication card 24. In some embodiments, the communication card is anethernet card. Additionally or alternatively, the communication card canbe a Bluetooth card which provides wireless communication capabilities.

[0039] The transport device 10 is mounted to the applicator 12 with anelectromagnet 26. To disengage the transport device 10 from theapplicator, voltage to the electromagnet is simply turned off to breakthe magnetic coupling between the top of the transport device 10 and theelectromagnet 26. The applicator 12 also includes a vacuum pump 28 whichdraws a vacuum through a suction port 41 (FIG. 2A) to create a suctionbetween suction ports 60 (FIG. 2A) of the transport device 10 and theskin of the patient to attach the device 10 to the skin. Themicroneedles 14 are bent at about a 90° angle about ⅓ of the distancefrom the tip 62 to the other end 64 (FIG. 2A) of each microneedle.Accordingly, as a rotary actuator 30, such as a stepper motor, shapememory alloy, contractile polymer, rotary solenoid, or any othersuitable rotary actuator, rotates the transport device 10 and thus movesthe mirconeedles 14, they penetrate laterally into the skin since thesuction produced by the vacuum pump 28 also draws the skin into thesuction ports 60 above a plane defined by the tip portions 62 of themicroneedles. An impedance sensor 32 is used to indicate when themicroneedles have sufficiently penetrated into the skin. A piezoelectricor a speaker 34 is also used to provide audible, perhaps verbal,indications to the user. The operation of the transport device 10 andapplicator 12 will be described below in greater detail.

[0040] Referring now to FIGS. 2A and 2B, in addition to a base portion36 which holds the microneedles 14, the transport device 10 includes acontrol unit 38 and a drug vial 40. The control unit 38 is provided withelectrical connections 42 which facilitate communication between thedevice 10 and the applicator 12, control electronics 43, and varioussensors 44 that measure, for example, impedance, pressure, temperature,injection flow rate, as well as other sensors. Any of these sensors canalso be located in the applicator 12, such as a pressure sensor 37. Thecontrol unit 38 also includes a power source 45 such as a supercapacitorand batteries which provide power to the device 10.

[0041] The drug vial 40 includes a drug chamber or reservoir 46 definedby a flexible membrane 48 and a rigid top section 50. Located above thedrug vial 40 in the control unit 38 is an actuator 52. The actuator 52is provided with a rigid base 54 that is joined to a cap 56 with aflexible bellow 58, or any other suitable expanding material, defining achamber 59. As illustrated in FIGS. 2C and 2D, the suction ports 60 arelocated at the bottom of the base portion 36 to provide access for thetips 62 of the microneedles 14 to the skin.

[0042] In use, the applicator 12 is turned on by the user, such as amedical clinician, to activate the electromagnet 26 to attach the device10 to the applicator 12. The user then delivers the device 10 to theskin. Next, the vacuum pump 28 creates a vacuum seal through the vacuumports 60 with the skin to hold the device 10 in place, and also to makethe skin more accessible to the microneedles 14 as discussed above.

[0043] Referring to FIG. 3, the vacuum pump 28 draws a suction,indicated by the arrows A, in the ports 60 to bring the skin up to thenecessary height in the ports. The rotary actuator 30 then rotates andhence moves the microneedles 14 towards the skin in a direction at orabout right angles to the direction of movement of the skin as it issucked into the openings 60. Once the microneedles 14 contact the skin,they continue to move in the same direction approximately 50 μm toseveral mm into the skin, thereby penetrating the sidewall of the raisedskin as illustrated in FIG. 4. In one embodiment, the penetration depthis approximately 200 μm. The extent of movement in this direction isdictated by the depth of the stratum corneum at the site where themicroneedles 14 penetrate the skin. As stratum corneum depth varies, theapplicator 12 uses the impedance sensor 32 to determine when the stratumcorneum has been transversed. The impedance sensor 32 measures impedanceof electric current flow between two of the microneedles 14. Impedanceis high in the stratum corneum, and drops dramatically in the portion ofthe dermis just below the stratum corneum (see, e.g., FIG. 9B whichshows a drop of approximately three orders of magnitude). The sensor 32reads the change in impedance as the microneedles 14 penetrate into theskin, and movement is stopped when the impedance drops by an order ofmagnitude.

[0044] Additionally or alternatively, there can be a hard mechanicalstop, for example, the top of the ports 60, that prevents themicroneedles from penetrating too deeply.

[0045] At this point, the vacuum pump 28 and the electromagnet 26 arede-activated to disengage the device 10 from the applicator 12. Thevacuum seal between the device 10 and the skin is no longer needed tosecure the device to the skin since the device 10 is now attached to theskin with the microneedles 14.

[0046] The control unit 38 of the device 10 then activates the actuator52 which operates in the illustrated embodiment by an electrolyticprocess to cause the volume within the chamber 59 to increase and henceforcing the cap 56 against the rigid top section 50 of the drug vial 40,thereby pushing the drug vial 40 downwards. Consequently, the flexiblemembrane 48 is pushed against a bowed section 68 of a base plate 39,while the ends 64 of the microneedles 14 pierce through the membrane 48and into the reservoir 46. Compression of the membrane 48 into thereservoir 46 expels the pharmaceutical through hollow pathways or boresof the microneedles into the skin. Thus, the device is able to deliver apharmaceutical to a precise location just below the stratum corneum ofthe skin, as indicated by the letter B in FIG. 3.

[0047] Once the correct dose of the pharmaceutical is delivered, thedevice 10 is re-attached to the applicator 12 and the rotary actuator 30moves the microneedles out of the skin to disengage the device 10 fromthe patient. Typically, the base portion 36 and the drug vial 40 arediscarded, while the control unit 38 is re-used. The device 10 is usedto deliver precise amounts of drugs as needed by a patient. Informationrelating to the patient can be relayed through an associated computer tothe device 10 and the applicator 12 via the communication card 24.

[0048] The same device 10 can be used for collecting fluid, such asinterstitial fluid, from the dermis. For collection to occur, thereservoir 46 must first be compressed. This is accomplished by movingthe drug vial 40 downward with the actuator 50 such that the membrane 48of the reservoir 46 is compressed to expel any air in the reservoir 46.Upon penetration of the microneedles into the skin, the expansionchamber 59 of the actuator 52 is contracted to allow the drug vial 40 torise which creates a vacuum inside the reservoir 46 to draw fluidthrough the microneedles into the reservoir 46.

[0049] Thus, the actuator 52 acts as a pump which facilitates pumping adrug through the microneedles into the skin or collecting a sample fromthe patient. The actuator 52 can be used to create a vacuum within thereservoir 46 before the device 10 is placed against the skin. In sum,the actuator 52 provides controlled, programmable transport to and fromthe target site.

[0050] The various features of the transport device 10 and theapplicator 12 will now be described in greater detail.

[0051] In the present application, the term “microneedle” is intended tobe construed as singular or plural, unless specifically modified by aterm indicating the number of microneedles. Microneedles disclosedherein may be porous or non-porous, uniform or of varying diameters orcross-sectional geometries, or some combination thereof. Hollowmicroneedles with uniform diameter are sometimes referred to asmicrotubes. As used herein, the term “microneedle” refers to bothmicrotubes and any other kind of microneedle as described previously.Additionally, microneedles may also have openings at either or bothends, as well as, on the side-walls at various and/or multiple positionsalong the length, or any combination thereof. Further, either or bothends of the microneedle may be flat, tapered to a point, rounded, orbeveled from one or more sides, as described below.

[0052] As shown in FIG. 4, the tip 62 has an opening 71 and is cut at anangle, α, of approximately 100° to 60°, to provide a slanted surface 66a. This surface 66 a and/or the outer surface 66 b can be beveled. Theillustrated embodiment has four microneedles 14, but there can be tenmicroneedles or more. The microneedles 14 are metal welded or solderedto the base plate 39, made from, for example, stainless steel, of thebase portion 36, and the bellows 58 is formed of a polymer and isultrasonic welded to the base 54 and the cap 56 of the actuator 52, orthe bellow can be permanently attached to either the control unit 38 orthe drug vial 40. Alternatively, these parts may be fitted together viaa thermal seal or any other suitable technique for forming a fluid-tightseal. Note that the device 10 is in use or not, the microneedles 14 arealways contained within the base portion 36 and never extend outside ofthe suction ports 60 beyond the bottom of the base portion 36. Thisminimizes or eliminates contamination of the microneedles and accidentalcontact between the needles and a patient or medical clinician.

[0053] The beveled surfaces 66 a and/or 66 b of the tip 62 has manyadvantages. It reduces the trauma to the skin; it further reduces anypain felt by the subject; it prevents coring of the tissue into themicroneedle; and it decreases the amount of force required forpenetration into the skin. Particularly, in regards to coring, sharptipped microneedles having a small inner diameter are less likely toaccumulate tissue within the hollow opening, thereby avoiding transportblockage. In the above embodiment, both ends of each microneedle 14 aresharpened: one end for insertion into the skin, and the other end forinsertion through membrane 48 into the reservoir 46.

[0054] In certain embodiments, as illustrated in FIG. 5, themicroneedles 14 can have holes 73 on the side-walls at various and/ormultiple positions along the length through which fluid can betransmitted, combined with the openings 71 (FIG. 4) or with solid tips75. There can be from one to 20 or more holes 73. The spacing betweenthe holes is approximately in the range of 100 μm to 2 mm.

[0055] The microneedles 14 may be manufactured from a variety ofmaterials and by a variety of methods. Representative materials includemetals, ceramics, semiconductors, organics, biodegradable andnon-biodegradable polymers, glass, quartz, and various composites.Representative methods include micro-fabrication techniques. In theabove illustrated embodiment, the microneedles 14 are made of medicalgrade stainless steel, such as 304 stainless steel. Stainless steelmicroneedles are advantageous because they are durable, semi-flexible,and have the mechanical strength to endure insertion into the stratumcorneum. They can be cut from readily available, relatively inexpensivecommercial stock via a chemical saw, or any suitable technique, to thedesired dimensions, and ground to the desired tip geometry.

[0056] The microneedles 14 have an inner diameter of about 10 μm to 100μm, an outer diameter of 30 μm to 250 μm, and a length of approximately5 mm to 10 mm. In the above illustrated embodiment, each of themicroneedles has an inner diameter of 54 μm, and an outer diameter of108 μm. Other embodiments use microneedles with an inner diameter ofabout 100 μm and outer diameter of about 175 μm.

[0057] The microneedles 14 can also be coated on the outside, theinside, or both. Coatings can cover part or all of either or bothsurfaces. Coatings can be selected from, but are not limited to, thegroup consisting of lubricants, chemical or biological reactionelements, and preservatives.

[0058] The microneedles may be made of one or more rows of microneedlesof uniform or varying dimensions and geometries, with uniform or varyingspacing, at uniform or varying projection angles, and any combinationthereof. In the embodiment above, the set of microneedles form acircular array of four microneedles. The array has a radius ofapproximately 5 mm to 20 mm. In the illustrated embodiment, the radiusis about 12 mm. In another embodiment, the set may include more than onecircular array of microneedles. In yet another embodiment, themicroneedles are arranged in an X by Y array, where X may or may notequal Y.

[0059] Additionally, as described above, the microneedle is bent, atapproximately a 90° angle. As shown in FIG. 3, the bend of around 90° ispositioned such that the segment from the bend to the tip 62 of themicroneedle is long enough to penetrate through the stratum corneum.However, the angle, curvature, and location of the bend in themicroneedle, as well as the orientation of the microneedle with respectto the device 10, can vary. For example, the bend angle may be 90° ormore or less, but typically less than 180°.

[0060] In the bent microneedle embodiment, the bevel side 66 a facesaway from the bend and towards the skin surface, prior to insertion ofthe microneedle into the skin, and continues to face away from the restof the device once it is inserted. Penetration occurs at “acute-angleinsertion” of the microneedle. The angle of insertion, β, (FIG. 3) isthe angle formed by the skin surface and the microneedle 14, with thevertex of the angle at the point of contact between the microneedle andthe skin surface. Acute-angle insertion reduces the associated painrelative to 90° insertion. The microneedle, with varying bend angle, canbe oriented for an insertion angle from 0° to 90°. Where the microneedleis close to or perpendicular to the skin at the entry site, a clearpathway for the substance to exit the skin is created upon withdrawal ofthe microneedle, resulting in leakage. Delivery of a complete dose of asubstance under the stratum corneum is improved by the low acute angleinsertion, especially when coupled with the downward facing beveled tip.The substance will more readily move down through the dermis. Moreover,with a low acute angle insertion, one has better control of the needleinsertion depth.

[0061] Referring to FIG. 6A, there is shown a plot of insertion force ofa needle versus penetration depth, illustrating the skin and needlebehavior as described by the various labels. After the needle touchesthe skin, the skin is deformed until a first point of puncture, afterwhich the needle slips. Subsequently, the needle deforms the secondlayer of skin until a second point of puncture, after which the needleslips again. Then the skin slides up the shaft of the needle. As theneedle is pulled out, the skin is also deformed, as shown in the bottomportion of the graph.

[0062] Turning now to FIGS. 6B-6I, a sequence of graphs illustrate theinsertion force [N] versus penetration depths [mm] profiles for 100 μm(top graphs, FIGS. 6B-6E) and 570 μm (bottom graphs, FIGS. 6F-6I)needles that are at an angle of 15° to 90° with respect to the surfaceof the skin and for needle insertion velocities of 0.1 and 1.0 mm/s. Asis evident from the figures, the smaller needles have significantlysmaller penetration forces. The figures also show that the velocity ofneedle insertion does not significantly affect the penetration forces.Finally, the figures show that needles inserted at smaller angles (forexample, 15°) to the surface of the skin require smaller penetrationforces. The peak insertion force for a 100 μm needle into the skin at a90° angle at a velocity of 1 mm/s is approximately 250 mN (FIG. 6E),while the peak insertion force for a 100 μm needle into the skin at a15° angle at a velocity of 1 mm/s is approximately 175 mN (FIG. 6C).

[0063] Thus, the microneedles 14 need not be parallel to the skin. Theycan be angled downward, for example, to facilitate penetration into theskin. The base 36 can be pushed against the skin so that portions of theskin will rise within access ports similar to the suction ports 60.

[0064] The rigid top section 50 of the reservoir 46 is made fromstainless steel, glass, such as Type I or Type II high purity glass, orpolymer, and the flexible membrane 48 is approximately 20 μm to 300 μm,preferably 100 μm, thick, and is made from a deformable elastopolymersuch as silicone rubber or any other suitable flexible material. Thereservoir 46 is typically filled with one or more pharmaceuticals fordelivery to the patient, and then sealed.

[0065] In the embodiment shown in FIGS. 2A and 2B, the reservoir 46 is asingle-chambered, hollow container with one rigid top section 50, andone deformable membrane 48. The reservoir 46 has a maximum fillthickness of approximately one to 5 mm, preferably about 2 mm, and avolume capacity approximately in the range of 100 μl to 5 ml

[0066] In the device 10, the microneedles 14 are in contact with thepharmaceutical in the reservoir 46 when the ends 64 of the microneedlesare inserted into the reservoir. There can be a semi-permeable membrane,filter, or valve placed between the reservoir 46 and the openings at theends 64 of the microneedles. The membrane or filter can serve to purifythe substance, or remove a selected material from the substance enteringor leaving the reservoir. A membrane or filter can also contain abinding partner to the selected material, thereby capturing or trappingthat material during the transport. The binding partner can be specificor nonspecific. A valve is useful in preventing leakage as well as inprecisely releasing a set amount of substance. The valve is also usefulto prevent backflow of a collected fluid through the microneedles. Insome embodiments, a microvalve is opened in each microneedle 14 to allowmovement of fluid for delivery or collection. For example, themicrovalve could be embedded in the microneedles 14 or be part of thereservoir 46. Alternatively, a non-permeable membrane, covering forexample the end of the microneedle opening into the reservoir, can bebreached to allow the fluid movement.

[0067] Rather than being a hollow chamber, in some embodiments thereservoir 46 can be a porous matrix, single or multi-chambered, or anycombination thereof. The reservoir 46 can contain one or more chambers.Each chamber can be the same or may differ from any or all of theothers. For example, a reservoir 46 can have one chamber that contains areagent and into which fluid is drawn through the microneedles. Areaction might then occur in this first chamber, the results of whichmight trigger manual or automatic release of a substance from the secondchamber through the microneedles into the skin.

[0068] The reservoir 46 is easily loaded with a substance to bedelivered. Loading can occur before or after association of thereservoir 46 with the microneedles 14. As mentioned earlier, theformulation can be one or more non-liquid drugs (for example, that havebeen dehydrated) that may be preloaded into the reservoir and thenreconstituted before delivery. In some embodiments, the inside of thereservoir 46 is coated with a material prior to assembly of thereservoir. The coating can have one or more purposes, including, but notlimited to, aiding flow so that the substance exiting or entering thereservoir moves smoothly and/or does not leave behind droplets, servingas a reactant used for detecting the presence or absence of a particularmaterial in the fluid, and/or serving as a preservative.

[0069] When the transport device 10 is used to deliver drugs, thereservoir 46 stores one or more drugs in one or more chambers to bedelivered to the target site. The reservoir 46 can be filled with thedesired drug through an opening situated opposite the placement of themicroneedles 14. Alternatively, the desired drug can be drawn up intothe reservoir 46 through the microneedles or the desired drug can beplaced within the reservoir 46 when it is sealed.

[0070] When the transport device 10 is used to obtain samples from thepatient, the reservoir 46 stores, in one or more chambers, one or morebiological samples drawn from the patient. The device can include one ormore elements directed at securing the sample within the reservoirduring removal of the device from the skin. These elements might includevalves, flaps and the like.

[0071] Although in the embodiment illustrated in FIGS. 1 and 2 a vacuumseal is initially used to secure the device 10 to the skin, alternativemechanisms for securing the device 10 on the skin are available thatinclude, but are not limited to, one or more straps, tape, glue, and/orbandages. The outer casings of the control unit 38, the drug vial 40,and the base portion 36 can be made of any stiff material, such as, butnot limited to, stainless steel and other hard metals, plastics, wovenor matted stiffened fibers, cardboard, and wood.

[0072] The actuator 52 disclosed herein facilitates pumping a drugthrough the microneedles into the skin or removing a sample from thepatient. The actuator 52 can be used to create a vacuum within thereservoir 46 before the device 10 it is placed against the skin. Theactuator 52 provides controlled, programmable transport to and from thetarget site.

[0073] In the illustrated embodiment, the actuator 52 operates by anelectrochemical reaction, in particular electrolysis of water (H₂O) thatconverts water into hydrogen (H₂) and oxygen (O₂) gas. There are twoelectrochemical reactions taking place: oxidation is occurring at theanode according to the reaction

2H₂O(l)→O₂(g)+4 H³⁰ (aq)+4e ⁻

[0074] and reduction is occurring at the cathode according to thereaction

2H₂O(l)+2e ⁻→H₂(g)+OH⁻

[0075] To keep the numbers of electrons balance, the cathode reactionmust take place twice as much as the anode reaction. Thus, if thecathode reaction is multiplied by two and the two reactions are addedtogether, the total reaction becomes

6H₂O(l)+4e ⁻→2H₂(g)+O₂(g)+4 H⁺(aq)+4OH ⁻(aq)+4e ⁻

[0076] The H⁺ and OH⁻ form H₂O and cancel species that appear on bothside of the equation. The overall net reaction therefore becomes

6H₂O(l)→2H₂(g)+O₂(g)

[0077] Hence, three molecules (1O₂, 2H₂) are produced per 4 electrons.That is, the number of moles of gas created by electrochemicaldecomposition of water as described by the following equation is

n _(gc) =n _(ge)/(eN_(A))=7.784×10⁻⁶mol/C

[0078] where n_(ge) is the number of molecules of gas produced perelectron put into the system, ¾, e is the charge of one electron, andN_(A) is Avogadro's number. This conversion results in a large volumechange of over, for example, three orders of magnitude, which isharnessed to expel the drug from the reservoir 46. When the conversionof water to hydrogen and oxygen occurs, the expansion compresses theflexible membrane 48, expelling the drug and any carriers or othercompounds or solvents out of the reservoir 46 through the microneedles14.

[0079] Referring in particular to FIG. 7A, there is shown the actuator52 by itself for illustrative purposes. The chamber 59 contains, forexample, 1 μl to 10 ml, preferably,1 μl to 1 ml, of water with 1 M ofNa₂SO₄ or NaOH. To initiate the electrolytic process, a current, I, isapplied to two electrodes 72 positioned within the chamber 59 of theactuator 52. Each electrode 72 can be solid or a mesh. The meshconfiguration provides a larger surface area to initiate thedecomposition process. The electrodes can be made of stainless steel,platinum, or platinum/iridium gauze, such as Alfa Aesar #40934, or anyother suitable material.

[0080] Referring to the graph depicted in FIG. 7B, there is shown arepresentative voltage to current relationship for the actuator or pump52 with two 3 mm×12 mm×50 μm thick stainless steel electrodes. FIG. 7Cshows the voltage to current relationship for the actuator 52 with two40 mm long Nichrome electrodes. Both FIGS. 7B and 7C show that nocurrent is drawn, and therefore no gas is created, until the voltagereaches approximately 1.7 V. At this point, the current drawn by thepump begins to increase almost linearly until the current reachesapproximately 115 mA, where it reaches steady state. The current versusvoltage slopes for the linear region are different based on theelectrode materials and configuration. For the pump 52 with stainlesssteel electrodes (FIG. 7B), the pump reaches steady current consumptionat approximately 3.8 V, while the pump with Nichrome electrodes (FIG.7C) reaches steady current consumption at approximately 2.5 V.Furthermore, at an operating current of about 10 mA, the operatingvoltage is about 2.5 V and 1.79V for the stainless steel electrodes, andthe Nichrome electrodes, respectively. The electrolytic process can beeasily stopped and if desired initiated again, and this process can berepeated to precisely control the expansion rate of the chamber 59 andhence the drug delivery rate of the device 10.

[0081] The actuator 52 can be a micro-electric motor, such as, forexample, Lorentz force or electrostatic motors, or operate by chemicalor electrochemical reactions, contractile polymers, shape memory alloys,or any other suitable mechanism to facilitate the transport of thepharmaceutical. Alternatively or additionally, the actuator can includemechanical or organic members, such as micro-valves or permeablemembranes, respectively, to further control transport rates. Theactuator 52 can also be any other suitable micro-mechanism, such asmotors, levers, pistons, solenoids, magnetic actuators, and the like,for controlling the motion of the flexible membrane 48 of the drug vial40 to provide precise and controlled delivery of compounds and/orcollection of body fluids.

[0082] In certain embodiments, the actuator 52 operates as a vaporgenerator. Liquid water, for example, contained in the chamber 59 of theactuator 52 is heated with an on-board heater which causes the liquid tochange to steam resulting in a significant increase in volume. In suchembodiments, the volume of the liquid water is about 500 nl to 5 μl. Thetemperature of vaporization of water is 100° C., and at that temperaturethe latent heat of vaporization is 2.25 kJ/kg. Thus for 1 μl of liquidwater, the steam volume becomes approximately 1.706 ml.

[0083] Alternatively, the top section 50 of the reservoir 46 can beformed from a conducting polymer, such as polypyrrol, which contracts(usually in one direction) under the application of a low voltagecurrent. The conducting polymers act like human muscle, that is, theycontract lengthwise. The force produced per area of these polymers isabout 1 to 10 Mpa, which is about a factor of 10 greater than that ofhuman muscles. The change in length of these polymers is about 2%.Contraction of the conducting polymer forces the drug and any carriersor other compounds or solvents out of the reservoir 46.

[0084] When the device is used to collect samples, the actuator 52functions as a reversible actuator to facilitate transport from thetarget area to the reservoir 46. For example, in the conducting polymerpump system, initial application of a low voltage current compresses thetop section 50, emptying the reservoir 46. While the reservoir is in itscontracted state, the device 10 is applied to the target site. Thevoltage is then disrupted to allow the polymer to expand to its naturalstate. Expansion of the reservoir 46 creates a vacuum inside thereservoir, which causes fluid to be drawn into the reservoir.

[0085] Another embodiment of the actuator 52 is a shape memory alloy orcontractile polymer wrapped around a circle. The actuator forms a twistthat is guided along a thread so that there is a linear (vertical)motion which places a force on the drug vial 40, thereby expelling thedrug from the reservoir 46. The actuator is returned to its initialretracted state by one of many available means that includes but is notlimited to shape memory alloys, springs, and super-elastic metal.

[0086] Recall, the vacuum pump 28 of the applicator 12 creates a suctionto draw the skin in one direction into the openings 60 of the transportdevice 10, and the rotary actuator 30 provides an orthogonal directionof motion of the microneedles 14 to facilitate acute-angle insertioninto the skin with the bent microneedles 14.

[0087] In other embodiments, these orthogonal motions may beaccomplished by use of one or more actuators. For example, an actuatorcan be used to move the microneedles in a direction perpendicular to theskin surface so that the bent portion of the microneedle are parallel toand come into contact with the skin, with the microneedle tip openingfacing the skin. The actuator continues to move the microneedles in theperpendicular direction, causing them to depress the skin under themicroneedle, and resulting in the neighboring skin being above the levelof the microneedle tips. The rotary actuator 30 then moves themicroneedles 14 forward in the direction of the microneedle tip 62,parallel to the skin surface. The microneedle tips 62 contact thesurface of the skin at the side of the depression formed by the initialperpendicular motion of the microneedle. The rotary actuator 30continues to move the microneedles in the parallel direction causing themicroneedles to penetrate the stratum corneum. When the microneedle tip62 has reached the target site, the rotary actuator stops the motion.One or more actuators can be involved in each motion. Again, a stopsignal can be generated using the impedance sensor system 32, discussedin detail below. Alternatively, there can be a hard mechanical stop orthe insertion motion can be stopped after a defined distance ofpenetration, or a defined period of time of insertion. Removal of themicroneedles 14 is accomplished in basically the reverse order.

[0088] Any of the foregoing embodiments, as well as any other applicableto the situation, could be synchronized with the impedance sensor 32,discussed in detail below, so that the drop in impedance, uponpenetration through the stratum corneum, triggers the pumping action ofthe actuator 52, such as the electrolytic, chemical reaction, polymercontraction actuators, or an electric motor or any other actuators usedin the device 10.

[0089] In certain embodiments, the device 10 is provided with contoured,drilled tunnels or guide sleeves through which the microneedles 14 areguided into the skin.

[0090] For safety and other reasons, the microneedles 14 can have capsor holsters covering the tips 62, as discussed previously, requiringadditional movement of the device 10 as a first step to uncap themicroneedles 14. The caps can be fastened to a moveable part within thedevice 10, and this part is moved by an actuator away from themicroneedle tips to uncap the stationary microneedles 14. In anotherembodiment, the caps may be a free-standing structure that is manuallyremovable prior to application, or the microneedles may penetratethrough the protective caps prior to application.

[0091] In some embodiments, the transport device 10 and/or theapplicator 12 is combined with an oscillator system, made from, forexample, a piezoelectric crystal, to assist the insertion of themicroneedles 14. The oscillator system can be an independent system,integrated with the actuators, or some combination thereof. Preferably,the microneedles are vibrated at 10 kHz in the direction of thepenetration motion. A potential advantage of using such an oscillatorsystem is that less force may be required to penetrate the skin.

[0092] As discussed above, the device 10 includes electrical sensors,such as the impedance sensor 32 which detects penetration of the stratumcorneum. That is, the sensor 32 signals when the desired insertion ofthe microneedles 12 have been achieved. The determination of thelocation of the microneedle tip(s) within or through the stratum corneumallows for delivery of a complete, predetermined dose to the patient ata location amenable for absorption by the patient's body.

[0093] This is accomplished by measuring impedance of the tissue as themicroneedles proceed through it. As the stratum corneum creates a highlevel of impedance, and the tissue beyond the stratum corneum onlyprovides a relatively low level of impedance, impedance is monitored todetermine when the microneedles have passed through the stratum corneum.At that point insertion may be stopped so as to avoid penetrating theskin layer containing nerves and capillaries.

[0094] In particular, as illustrated in FIG. 8A, a low voltage circuitis formed with two of the microneedles 14 acting as electrodes. Becausethe dry stratum corneum of the epidermis 90 acts as a capacitive barrierwhile the sub-epidermal layers 92 are well conducting, the impedanee ofthe circuit drops as the microneedles pierce through the stratum corneum90. The change in impedance is by one or more orders of magnitude andreliably indicates when the microneedles have pierced through thestratum corneum 90. Furthermore, at less than 1 Volt, the voltagestimulus is not felt by the subject. Note that the microneedles 14 areelectrically isolated from the base. An illustrative embodiment of acircuit diagram of the circuit used here is shown in FIG. 8B, where theZ_(load) represents the unknown impedance.

[0095] As an example, impedance measurements of pig skin is illustratedin FIG. 9A. The top portion 94 of the graph illustrates the measuredimpedance of pig skin over a frequency range before a microneedlepenetrates the stratum corneum and the bottom portion 96 represents themeasured impedance after the microneedle has penetrated the stratumcorneum. As can be seen, the difference between the two portions 94 and96 of the graph can be over three orders of magnitude. Turning also toFIG. 9B, there is shown a plot of impedance versus the perpendiculardepth into the skin, which clearly illustrate that the penetration intothe skin produces smaller impedances.

[0096] Rather than sweeping over a frequency range, the input signal ofthe impedance sensor 32 can be set at one frequency. The input signalcan be a square wave generated by an embedded processor such as aTI-MSP430F149IPM, produced by Texas Instruments of Dallas, Tex. Certaincharacteristics of this chip are that it draws 35 μA when active, andless than 1 μA in low power mode, and has a 64 pin PQFP package, a 1.8to 3.6 V power supply, 8 analog to digital converters, 60 kbytes offlash memory, 2 kbytes of RAM, 2 16-bit timers, and an on-chipcomparator. Alternatively, a processor such as a TI-MSP430F110IPW can beused. This chip draws 35 μA when active, and less than 1 μA in low powermode, and includes a 20 pin TSSOP, 1.8 to 3.6 V power supply, 1 kbyte offlash memory, 128 bytes of RAM, and a 16-bit timer. Regardless whichprocessor is used, the output signal can be pulse width modulated, andthe impedance sensor 32 can be provided with a log transformer tocompress the output signal to within the range of the analog to digitalconverter of the processor.

[0097] As mentioned earlier, in certain embodiments, a glucose sensor isassociated with the transport device 10. In these embodiments, fluid iswithdrawn from the patient through the microneedles 14 into one of amultiplicity of reservoir chambers. The glucose sensor is at leastpartially in one of the chambers, where it can detect the concentrationof glucose in the fluid. Information from the glucose sensor is read andinterpreted by the operator of the device 10, for example, with the useof the display 22 of the applicator 12, who can then activate anotherchamber of the reservoir to deliver the appropriate amount of insulin tobring the glucose concentration to an appropriate level. Alternatively,the procedure can be automated so that the glucose sensor reads theglucose concentration in the fluid, and, based on that concentration,sends a signal, such as an electronic signal, to the other chamber,“telling” that chamber whether or not to deliver insulin through a setof microneedles, and how much insulin to deliver.

[0098] In any of the above describe embodiments, one or more controllerssuch as a programmable microprocessor located in the transport device 10and/or the applicator 12 can control and coordinate the actuators,pumps, sensors, and oscillators. For example, the controller caninstruct the actuator 52 to pump a specified amount of drug into apatient at a specified time. The specified amount may be the full amountcontained in the reservoir 46 or a partial amount. Thus, the device isable to inject a partial or full amount of drug incrementally over adesired time period. One controller may control the operation of theapplicator 12, while another controller controls the operation of thedevice 10. Alternatively, a single controller may control the operationsof the applicator 12 and the device 10. In any case, the applicator 12and/or the device 10 can communicate with each other or with a centralprocessor, for instance, using wireless communications capabilitiesprovided with either or both the applicator 12 and the device 10.

[0099] The transdermal transport device 10 is not limited to theembodiments described above. For example, other embodiments of thetransdermal transport device 10 are shown in FIGS. 10 and 11, where likereference numerals identify like features.

[0100] In the device 10 of FIG. 10, the microneedles 14 are again bentat about a 90° angle. They are oriented so that there is a section thatis parallel to the surface of the skin S and a section that isperpendicular to the base 36 of the device 10. The microneedles 14 aresoldered or attached in any suitable manner to a needle plate 100 thatis able to turn, but not able to translate. In this embodiment, themicroneedles 41 are not inserted into the drug vial 40 until just beforedelivery. The pump assembly or actuator 52 is pinned in place by threepins that slide in angled slots 101 as the inner portion of the device10 is turned. For extra guidance and stability, the actuator 52 alsorides on pins 102 in slots that are cut into the actuator 52.

[0101] The device 10 is first brought to the skin S by the applicator 12(FIG. 1). The electromagnet 26 in the applicator 12 turns the insideportion of the device 10, which causes the actuator 52 to translate downonto the ends 64 of the microneedles 14 as the needles are turned intothe skin S while suction is being applied through the ports 14 to drawthe skin S into the suction ports 60. Thus, the back ends 64 of themicroneedles penetrate the vial 40 as the front ends penetrate the skin.Alternatively, the back ends 64 of the microneedles can already be inthe vial 40, while the front ends are provided with caps through whichthe needles penetrate, or are removed before inserting the needles intothe skin. The drug in the reservoir 46 is then pumped through themicroneedles 14 as the actuator 52 is activated.

[0102] The depth of insertion is controlled by hard stops 104 on thebase plate 36. The skin S is sucked into the suction ports 60 by vacuumup to these hard stops 104. Since the microneedles 14 soldered intoplace at a specific depth, and the hard stops can be set to a desireddistance from the plane of the needles, the depth of insertion cantherefore be controlled.

[0103] The actuator 52 is mounted on top of the vial 40, with theflexible membrane 48 positioned between the two. The electrodes 72 aremounted inside the actuator 52, and the leads come out directly into acircuit board 106, which is mounted just above the top of the actuator52. On the underside of the circuit board 106 are mounted the electroniccomponents 43, and on the top side is mounted the battery or powersource 45. The applicator 12 magnetically attaches to the battery 45 tohold and rotate the device 10, while electrical connection is madebetween the applicator 12 and the device 10 through the copper ring 42.

[0104] The device 10 of FIG. 10 has a height of about 15 mm, while thedevice 10 of FIG. 11 has a lower profile with a height of about 7 mm. InFIG. 11, the microneedles 14 are mounted such that they always remain inthe same plane of rotation. This helps reduce the overall height of thedevice 10, since open space between the ends 64 of the microneedles 14and the drug vial 40 is not necessary. The microneedles 14 can either bepermanently affixed as part of the drug vial 40, or as a separate ring.If the microneedles 14 are mounted on a separate ring, the actuator 52is rotated onto the back end 64 of the microneedles 14 before delivery.Then, the entire actuator/microneedle assembly is rotated into the skinS.

[0105] The depth of insertion is controlled by the space 200 between thebase 36 and the component 202 that couples the microneedles 14 to thevial 40. This component 202 could either be some sort of fluidic circuitor simply a ring that holds the microneedles 14 in place for insertioninto the vial 40, or the microneedles may be part of the vial 40. Vacuumsuction would still be used to draw the skin into the ports 60 beforeinsertion of the microneedles 14.

[0106] The actuator 52 is mounted as a ring around the vial 40. The topportion 204 of the actuator 52 is still above the vial 40, and theflexible membrane 48 is located between the top portion 204 and the vial40. However, most of the actuator 52 is placed round the outside of thevial 40. This helps reduce the overall height of the device 10. Theelectrodes can be mounted as ring electrodes directly from the circuitboard 106, which can also function as the top of the actuator 52. Thebattery 45 and the electronic components 43 are all mounted on the topof the circuit board 106.

[0107] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims. For example, the actuator or pumparrangements, such as the electrolytic actuator, can be used in othertypes of transdermal transport devices, as well, such as the devicesdescribed in the U.S. application Ser. No. 10/238,844, filed Sep. 9,2002, by Angel and Hunter, the entire contents of which are incorporatedherein by reference.

What is claimed is:
 1. A transdermal transport device, comprising: areservoir for holding a formulation of an active principle; one or moreneedles, each needle having a bore through which the formulation istransported between the reservoir and a biological body, each needlehaving an end portion that is substantially aligned in a plane parallelto a surface of the biological body when the device is placed on thesurface; and a vacuum generator which creates a suction to draw aportion of the surface beyond the plane of the end portions to enablethe end portions to penetrate the portion of the surface as the needlesare translated along an axis that is substantially parallel to theplane.
 2. The transdermal transport device of claim 1 wherein the vacuumis used to secure the device to the surface of the body.
 3. Thetransdermal transport device of claim 2 wherein the vacuum is turned offafter the needles penetrate the skin.
 4. The transdermal transportdevice of claim 1 wherein the needles are rotated about an axis that issubstantially perpendicular to the plane.
 5. A transdermal transportdevice, comprising: a means for holding a formulation of an activeprinciple; a means for transporting the formulation between the meansfor holding the liquid formulation and a target area of a biologicalbody; and a means for creating a suction to draw a portion of the targetarea towards the means for transporting to facilitate penetrating theportion of the target area with the means for transporting.
 6. A methodof transdermally transporting a formulation of an active principle,comprising: generating a suction to draw a portion of a target area of abiological body towards an array of needles of a transdermal transportdevice, each needle have an end portion which is substantially alignedin a plane parallel to a surface of the biological body; and driving theend portions into the portion of the target area.
 7. The method of claim6, wherein the suction secures the device to the surface of the body. 8.The method of claim 7, further comprising turning off the suction afterthe end portions have penetrated the portion of the target area.
 9. Themethod of claim 6, wherein driving includes rotating the end portions ofthe needles about an axis that is substantially perpendicular to theplane that is parallel to the surface of the biological body.